Non-insulin-dependent diabetes mellitus (type 2 diabetes) is a disorder of glucose homeostasis characterized by impaired insulin action (insulin resistance) and impaired insulin production. It is widely held that genetic factors play a key role in the development of insulin resistance and type 2 diabetes. Insulin resistance is inherited in as a non-Mendelian trait, the pathogenesis of which likely involves genetic heterogeneity and polygenic inheritance. We are interested in dissecting the genetic components of insulin resistance using mouse and human genetic models. The relative roles of insulin resistance and insulin deficiency in the genetics of diabetes are being dissected by generating mice carrying mutations in genes important for insulin action and beta cell development or insulin secretion. We hope to learn from these investigations whether insulin resistance and insulin deficiency share a common etiology, and which genes govern these complex metabolic events. An important offshoot of this area of research is the identification of modifier genes, i.e., alleles that determine the different susceptibility of different mouse strains to insulin resistance and/or beta cell failure. In the last two years, studies supported by this intramural project have led to the generation of animal models that have challenged the traditional views on the pathogenesis of type 2 diabetes and its genetic etiology. First, we have developed an oligogenic model of type 2 diabetes (the "NIDDM" mouse) in which we have demonstrated the importance of epistatic interactions in the etiology of non-Mendelian disorders, such as diabetes. Next, we have developed a tissue-specific model of insulin resistance, that changes the traditional view of diabetes as a disorder of insulin action in muscle and adipose tissue. These data have also been confirmed in a collaborative study with scientists at the Joslin Diabetes Center in Boston.